The present invention pertains to a process for the production of a specific crystal modification of a polymorphic, organic substance by precipitation of the specific crystal modification from the aqueous solution of the salt of the polymorphic substances using ordinary water-soluble organic solvents as additives as well as an acid or base.
The polymorphism of active substances is of great importance for chemical development, process development and the development of formulations. It is known that some organic substances occur in only one crystal structure, others (referred to as polymorphs) in two or more structures (known as modifications or crystal modifications). It is not possible to predict the number of crystal modifications, including their physiochemical properties, particularly their thermodynamic stability, as well as the different behavior after administration in living organisms.
It is known that for some polymorphs a particular modification represents the thermodynamically stable phase throughout the entire temperature range up to the melting point, whereas with other material systems there are one or more transition points at which the stability relationship reverses. In a range apart from this transition point, one particular modification is always thermodynamically stable. All other modifications that exist in this range are metastable and transform themselves sooner or later into the thermodynamically stable modifications. The time in which such a conversion takes place is specific to the material and depends on the kinetics of the material system. The material-specific kinetics also determine which modification is formed during a crystallization or precipitation process. It is not possible to predict the stability relationship of co-existent crystal modifications, especially the existence and location of the aforementioned transition points. Furthermore it is neither possible to predict the kinetics of the conversion of metastable modifications to stable ones nor to predict which modification will be formed in a crystallization or precipitation process. A review of the current state of knowledge regarding these fundamental thermodynamic and kinetic relationships is found in J. Bernstein, R. J. Davey. J. O. Henck. Angew. Chem. Int. Ed., 1999, 38, 3440–3461.
It is known that the formation of metastable modifications can be favored, although the driving force for the formation of the thermodynamically stable phase in a crystallization or precipitation process is the greatest. Since time within which a transformation of co-existent crystal modifications takes place is usually orders of magnitude longer than the time for phase formation in a crystallization or precipitation process, these products, which were formed in a metastable structure, typically remain in this state for the time being during the further production and processing steps. Some known examples of this behavior are given in J. Bernstein et al. (see above). Numerous problems can be caused, particularly with active substances, by using or processing metastable crystal modifications. These problems, caused primarily by undesired and uncontrolled crystal growth (recrystallization), can occur during manufacture, formulation, storage, transport or application and can cause significant changes in bioavailability, caking etc. (J. Halebian, W. McCrone, J. Pharm. Sci. 58 (1969) 911).
An example of such problems is 2-(2-chloro-4-mesyl-benzoyl)cycloliexane-1,3-dione hereinafter referred to as sulcotrione, which has herbicide properties and is used in the production of weed-killers. Sulcotrione occurs for example in two modifications (in this regard, refer to the German patent application no. 10152459.5, which as a whole is to be part of the present application). The metastable modification, hereinafter referred to as modification (I), is the product of a manufacturing process, which follows the description in EP-A2-0 186 117. Since this modification is metastable, it is less suitable for production, formulation, storage and application of this active substance than the stable modification.
Commonly applied methods for reproducible manufacture of the stable modification of a substance are evaporative or cooling crystallization, as well as recrystallization in a carefully selected solvent (see WO 97/49681 A1). The choice of an appropriate solvent is made with the objective of influencing the surface energy of the crystal with the surrounding solution and/or the complex formation of the molecules in the course of the crystallization in order to promote formation of the desired crystal structure (N. Bladgeni. Powder Technology, 121 (2001) 46–52; R. J. Davey et al., Crystal Growth & Design, 1(1), (2001) 59–65; U.S. Pat. No. 5,959,108; U.S. Pat. No. 5,939,555). In WO 01/64672 A1 for example, a process is described for obtaining a specific modification. It is based on the solution of the isomorph in butanone/water (10:1) with subsequent addition of an acid. The disadvantage of such strategies is that a solvent for crystallization found in this manner is only seldom suitable for the preceding process and reaction steps. Consequences of this are cost-intensive measures such as changing the solvent, or recrystallization of an already formed metastable crystal structure is necessary. In particular, such procedures are also usually associated with a significant loss of yield.
Another known method to have a targeted influence on the formation of specific crystal structures of a polymorphic substance is the use of so-called “tailor-made” additives (E. Staab et al., Adv. Mater., 2 (1990) 40). The objective of such “tailor-made” additives is likewise to influence the surface energy of the crystal with respect to the surrounding solution and/or the formation of molecular complexes during crystallization in order to promote the formation of the desired crystal structure (see for example U.S. Pat. No. 5,716,445 A). Characteristic of “tailor-made” additives is a partial conformance or similarity of the molecular structure to that of the polymorphic substance. The advantage of using such “tailor-made” additives compared to the aforementioned strategy is the possibility of use in different solvents, which makes the implementation of such a process simpler. However, as a rule the specifically designed additives must be synthesized exclusively for their use to exercise specific influence on the polymorphism, which makes their development time-consuming and makes the process in which they are used expensive.
It was therefore the task of the present invention to prepare a process for the manufacture of specific modifications that can be used for efficient, cost-effective recovery of specific modifications. In particular it was the task of the present invention to make available a process for obtaining the modification that does not require a change of solvent and/or recrystallization.
The challenge was solved in the present invention by using inexpensive and easy-to-use additives in order to achieve the formation of a specific crystal modification. These additives also show their effect in solvents used in the prior reactions and processing steps, so that a change of solvent and/or additional process steps can be omitted.
It was found that typical organic solvent molecules are outstandingly suitable additives for promoting the formation of specific crystal structures of organic polymorphic substances in acid/base precipitative crystallizations. Surprisingly, the production of specific modifications of polymorphic organic substances succeeds directly by precipitation of the specific crystal modification from the salt of the polymorphic substance in aqueous solution according to the following reaction equation,
whereby the precipitation of the substance in the desired crystal structure is promoted by addition of typical organic, water-soluble solvents as additives.
The term “additive” as it is used here refers to compounds or substances that are added to an existing solution of a substance, whereby the amount (w/w) of the additive applied is preferably less than the amount of substance present in solution. Preferably the additive in an amount that is 0.1 to 20% with respect to the amount of the substance to be precipitated; particularly preferable is an amount of 1 to 10% and especially of 1 to 5%. It does not matter here whether the additive is added to the available solution or whether said solution is added to an available additive or a solution containing the additive.